Physics-based simulation provides a powerful framework for understanding biological form and function. Simulations may be used by biologists to study macromolecular assemblies or by clinicians to analyze disease mechanisms. Simulations help biomedical researchers understand the physical constraints on these systems as they engineer novel drugs, drug delivery mechanisms, synthetic tissues, medical devices, or surgical interventions. We propose to establish the National Center for Simulation of Biological Structures (SimBioS). We will develop, disseminate, and support a simulation toolkit (SimTK) that enables users to create and visualize accurate models and simulations of biological structures at all scales-from atoms to organisms. SimTK will be an extensible, open source, freely available software system that will build on component software systems developed by the project participants and others. The software will be developed and tested in close collaboration with biomedical scientists to ensure its utility and accuracy. The initial driving biological problems will immediately exercise a full range of scales: simulating RNA folding, molecular machines, neuromuscular dynamics, and cardiovascular mechanics. We have identified the biocomputation research challenges that must be addressed in order to move beyond current capabilities. We have assembled a team of researchers with a track record of accomplishments in modeling, simulation and visualization of biological structures. The software engineering effort will be lead by experienced professionals, who have previously developed and delivered complex software packages to thousands of users. Our aggressive dissemination plan includes regular workshops, a national newsletter, and on-line training through Stanford's Center for Professional Development. Our planning effort has established the vision, facilities, training environment, administrative organization, and collaborative relationships required for the success of this challenging project. In the context of other centers focusing on complementary elements of biomedicine, our center is focused on the physical reality of biological structures. It will thus provide a critical piece of a national biomedical computing infrastructure.